1. Field
The field relates to organic aldehydes and derivatives thereof, and in particular to methods of administering pharmaceutical compositions containing such compounds to treat inflammatory diseases.
2. Description of the Related Art
Many acute and chronic inflammatory diseases are thought to be caused by pathological immune responses. Tissue injury caused by ischemia, reperfusion or physical trauma is aggravated by inflammatory reactions. The natural resolution of inflammation is often incomplete, leading to chronic pathological conditions associated with pain and functional impairment of the affected tissues. Although many drugs in present use reduce pain and inflammatory damage, there is still an urgent need for better treatments for a wide variety of inflammatory diseases.
Rheumatoid arthritis is a well known example of an inflammatory disease for which improved treatments are needed (Saravanan et al., Expert Opin. Pharmacother. 3:845-56 (2002); O'Dell, N. Engl. J Med. 350:2591-602 (2004)). Typically, rheumatoid arthritis patients are first treated with nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, indomethacin, ibuprofen and many others (Steinmeyer, J. Arthritis Res. 2:379-85 (2000)). These drugs inhibit the first step of prostaglandin synthesis by competitively inhibiting the enzymes cyclooxygenase 1 and 2 (COX-1 and COX-2). In general, NSAIDs provide only symptomatic relief from the pain and inflammation associated with the disease, and do not arrest the progression of pathological injury to the joints. Moreover, the use of these drugs is limited by side effects, in particular gastrointestinal ulcers that are thought to be caused by the inhibition of COX-1. More recently developed selective COX-2 inhibitors have fewer gastrointestinal side effects, but increase the risk of myocardial infarction (Ardoin et al., Curr. Opin. Rheumatol. 18:221-226 (2006)).
In contrast to NSAIDs, glucocorticoids are potent suppressors of immune responses and inflammation. However, the continued use of glucocorticoids at supraphysiological doses is associated with many adverse effects, some of which are severe, such as hypertension, increased susceptibility to infections, osteoporosis, growth arrest and behavioural disturbances. Withdrawal from corticosteroid therapy can lead to disease flare-up and also acute adrenal insufficiency.
Several other drugs that are able to reduce the progression of rheumatoid arthritis, at least in some patients, are collectively referred to as disease modifying anti-rheumatic drugs (DMARDs). Examples include methotrexate, chloroquine, sulfasalazine, gold salts, D-penicillamine, azathioprine, leflunomide and cyclosporine. DMARDs are now often used earlier in the course of disease (Scott, Arthritis Res. Ther. 6:15-8 (2004)). While these drugs may arrest or reduce the progression of joint destruction, they have a variety of adverse effects, some of which may be severe, leading to the withdrawal of the drug from the treatment schedule.
Recently, a significant improvement in the treatment of rheumatoid arthritis has been achieved with a novel class of DMARDs often referred to as biologics (Olsen et al., N. Engl. J. Med. 350:2167-2179 (2004)). Biologics are therapeutically effective proteins that are engineered and expressed using recombinant DNA technologies. Some important biologics currently used for the treatment of rheumatoid arthritis are tumor necrosis factor (TNF) neutralizing antibodies and TNF receptor constructs. These new anti-rheumatic drugs have a quicker onset of action than the traditional DMARDs, and suppress the progression of joint erosions. However, this class of drugs must be parenterally administered and is quite costly. Moreover, extended use of TNF neutralizing biologics has revealed adverse effects, such as reactivation of tuberculosis, increased susceptibility to infections, and an increased risk for development of malignant diseases (Mikuls et al., Drug Saf. 26:23-32 (2003)).
Because of the shortcomings of the existing drugs used for treating rheumatoid arthritis and other inflammatory diseases, extensive efforts are being made by the pharmaceutical and biotechnology industries to develop novel treatment modalities that are safe and effective (Kumar et al., Nat. Rev. Drug Discov. 2:717-26 (2003); Adcock, Drug Discovery Today: Therapeutic Strategies, 1:321-9 (2004); Smith, Drug Discovery Today 10:1598-1606 (2005)). One molecule that has been identified as potentially useful in treating inflammatory disease is carbon monoxide. Carbon monoxide (CO) is an endogenous metabolite with pleiotropic effects that are integrated into adaptive responses of the body to various types of stress (Ryter et al., Bioessays, 26: 270-80 (2004)). CO inhibits TNF production in vitro and in vivo, and has shown impressive anti-inflammatory effects in animal models (Otterbein, Antioxid. Redox. Signal. 4:309-319 (2002); Ryter et al., Bioessary 26:270-280 (2004)). In addition to inhibiting TNF production, CO has other anti-inflammatory effects. It inhibits the production of other pro-inflammatory cytokines, such as IL-1, IL-6 and MIP-1 (Otterbein et al., Nat. Med. 6:422-428 (2000); Morse et al., J. Biol. Chem. 278:36993-36998 (2003)), enhances IL-10 production (Otterbein et al., Nat. Med. 6:422-428 (2000)), inhibits excessive NO production by inducible nitric oxide synthase (Sarady et al., Faseb J. 18:854-856 (2004)), inhibits mast cell activation (Ndisang et al., Immunopharmacol. 43:65-73 (1999)), and modulates immune responses (Song et al., J. Immunol. 172:1220-1226 (2004)).
Often, however, endogenous carbon monoxide (CO) does not provide its full potential of beneficial effects, because its production is delayed or reduced under pathological conditions. Thus, therapeutic effects may be achieved by administration of exogenous carbon monoxide. Exogenous CO may also induce the expression of hemoxygenase-1 (HO-1) (Sawle et al., Br. J. Pharmacol. 145(6):800-810 (2005); Lee et al., Nat. Med. 8:240-246 (2002)). HO-1 is known to have a wide variety of protective functions (Otterbein et al., Trends Immunol. 24:449-455 (2003)), most of which are mediated by its products CO and biliverdin/bilirubin. Thus, the beneficial effects of exogenous CO may be further augmented by the induction of endogenous CO and biliverdin/bilirubin production.
Indeed, treatment of animals by inhalation of carbon monoxide has revealed beneficial effects in a variety of disease models. However, systemic delivery of carbon monoxide via the lung is not practical outside of hospitals, and is limited by the requirement for doses that are near toxic levels. Limitations of carbon monoxide inhalation therapy may be overcome by the use of carbon monoxide releasing molecules, also known as CORMs (Motterlini et al., Curr. Pharm. Des. 9:2525-39 (2003)). Impressive therapeutic effects of CO used as a gas and CORMs have been achieved in animal models of inflammation (Sarady et al., Faseb J. 18:854-6 (2004); Zuckerbraun et al., Am. J. Physiol. Gastrointest. Liver Physiol. 289: G607-13 (2005); Sawle et al., FEBSLett. 508:403-6 (2001)), ischemia/reperfusion injury (Amersi et al., Hepatology, 35:815-23(2002); Nakao et al., Am. J Pathol. 163:1587-98 (2003); Zhang et al., J. Biol. Chem. 278:1248-58 (2003); Vera et al., J. Am. Soc. Nephrol. 16:950-8 (2005); Sandouka et al., Kidney Int. 69:239-47 (2006)), postoperative ileus (Moore et al., Crit. Care Med. 33:1317-26 (2005)), transplantation (Chauveau et al., Am. J. Transplant. 2:581-92 (2002); Clark et al., Circ. Res. 93:e2-8 (2003); Gunther et al., Diabetes 51:994-9 (2002); Akamatsu et al., Faseb J. 18:771-2 (2004); Martins et al., Transplant. Proc. 37:379-81(2005)), atherosclerosis (Otterbein et al., Nat. Med. 9:183-90 (2003)), restenosis (Otterbein et al., Nat. Med. 9:183-90 (2003)), myocardial infarction (Stein et al., J. Mol. Cell. Cardiol. 38:127-34 (2005); Guo et al., Am. J. Physiol. Heart Circ. Physiol. 286:H1649-53 (2004)) and pulmonary hypertension (Zuckerbraun et al., J. Exp. Med. 203:2109-19 (2006)).
While the potential advantage of CO delivery by CORMs over CO delivery by inhalation is generally recognized, the identification of CORMs which selectively deliver CO to therapeutic targets remains a challenge in the development of CORMs as drugs. Selective delivery of CO to diseased tissues may be achieved by using compounds that release CO in the presence of reactive oxygen species, which are generated at high levels under many pathological conditions. Reactive oxygen species (ROS) include, without limitation, oxygen ions, superoxide, peroxynitrite, free radicals and peroxides, both inorganic and organic. A variety of highly reactive ROS are generated from superoxide (Hogg, Semin. Reprod. Endocrinol. 16:241-8 (1998)). These molecules are generated at low levels in many tissues, and have important roles in various signal transduction pathways (Droge, Physiol. Rev., 82:47-95 (2002)). However, excessive production of ROS occurs in many pathological conditions. While a variety of mechanisms have evolved to prevent damage by excessive amounts of ROS, conditions in which production of these highly reactive molecules exceeds the capacity to neutralize them are referred to as oxidative stress. “Oxidative stress” is a medical term for the damage to animal or plant cells caused by reactive oxygen species.
Oxidative stress is a hallmark of many diseases (Spector, J. Ocul Pharmacol Ther. 2:193-201(2000)). These include inflammatory diseases, such as rheumatoid arthritis (Bauerova et al., Gen. Physiol. Biophys. 18 Spec No: 15-20 (1999); Hadjigogos, Panminerva Med. 45:7-13 (2003); Hitchon et al., Arthritis Res. Ther. 6:265-78 (2004)), asthma (Andreadis et al., Free Radic. Biol. Med. 35:213-25 (2003); Henricks et al., Pulm. Pharmacol. Ther. 14:409-20 (2001)), ulcerative colitis (Suzuki et al., Scand. J. Gastroenterol. 36:1301-6 (2001)), and diseases associated with chronic inflammatory reactions, such atherosclerosis and neurodegenerative diseases (Beal, Free Radic. Biol. Med. 32:797-803 (2002)), and/or with ischemia/reperfusion injury, such as myocardial infarction (Frangogiannis et al., Cardiovasc. Res. 53:31-47(2002)), stroke, sleep apnea and transplantation. New CORM compositions that release CO in the presence of reactive oxygen species would be useful for treating inflammatory diseases such as these.